Gastric cancer worldwide is the second highest cause of death from cancer. While rates of gastric cancer have been decreasing in the United States, gastric cancer prevalence remains high in other parts of the world, especially in Asia. Presently, patients in endemic regions for gastric cancer, especially Japan and China, undergo screening by upper endoscopy. There is no alternative at present for discovery of early cancer other than by endoscopy. Grading of these endoscopies is based solely on hematoxylin and eosin staining. There are no prognostic markers that could indicate those at risk for future cancer development. Therefore, while biopsies can reveal early gastric cancers, patients in high risk regions who are initially negative by endoscopy must be followed with endoscopies in rule out future developments.
The epidemiological association between chronic H. pylori infection and gastric carcinoma is now well established, such that the Working Group Meeting of the International Agency for Research on Cancer with the World Health Organization recently classified Helicobacter pylori as a group 1 human gastric carcinogen (Peura, D. A. Gatroenterology. 113, S4-S8 (1997)). Parsonnet and colleagues reported that 84% of patients with gastric cancer had serum antibodies against H. pylori, as opposed to 66% of uninfected matched controls (Parsonnet, et al. New Eng. J. Med. 325, 1127-1131 (1991)). H. pylori infection induces a chronic gastritis progressing to atrophic gastritis, foveolar hyperplasia and intestinal metaplasia (Mobley, H. T. L. Gastronenterology. 113, S21-S28 (1997)). Recent studies have indicated that chronic gastritis associated with Helicobacter pylori contributes to the development of gastric adenocarcinoma (Peura, D. A. Gatroenterology. 113, S4-S8 (1997); Parsonnet, et al. New Eng. J. Med. 325, 1127-1131 (1991); Forman et al. Br. J. Med. 302, 1302-1305 (1991); Nomura, et al. New Eng. J. Med. 325, 1132-1136 (1991)). Nevertheless, the mechanism of progression from chronic gastritis to malignant disease remains unclear, and the relationship of intestinal metaplasia, H. pylori infection and the development of cancer continues to be controversial. Moreover, while an association between gastric cancer and infection with H. pylori has recently been established, the cell of origin for gastric adenocarcinoma is controversial. This does not establish a mechanism between the bacteria and the cancer, and provides little or no guidance for correlating treatment of, or risk associated with, H. pylori as it relates to development of gastric cancer.
It is therefore an object of the present invention to provide screening methods for early gastric cancer.
It is a further object of the present invention to provide means for assessing the degree of early gastric cancer and for screening and following patients at risk for gastric cancer.
It is a still further object of the present invention to provide means for serological testing for patients at risk of gastric cancer.
It has been determined that a specific metaplastic lineage that contains immunoreactivity for a trefoil polypeptide, spasmolytic peptide, is associated with and gives rise to the vast majority of human adenocarcinomas. The identification of this Spasmolytic Polypeptide Expressing Metaplasia (SPEM) is a major factor for grading of biopsies of the stomach to assess risk for gastric cancer. It also forms the basis of a method for serological screening for those at risk for gastric cancer. In a preferred embodiment, antibodies to spasmolytic peptide (hSP) are used in immunostaining of biopsies of gastric tissue obtained by endoscopy for grading biopsies. Those patients having these cells, characterized by a morphology more typical of a type of cell present normally in the intestine and not stomach, Brunner""s gland cells, are at risk of developing adenocarcinoma. Since these cells express hSP, antibodies or nucleic acid probes hybridizing to mRNA encoding hSP, can be used for rapid detection of the cells in tissue biopsies. The antibodies can also be used in serological tests for screening and following patients at risk for gastric cancer. In combination with evidence of previous or present invention with H. pylori, the tests are predictive of the likelihood of developing adenocarcinoma.